Diffuse Optical Imaging (DOI) is a non-invasive optical technique that employs near-infrared (NIR) light to quantitatively characterize the optical properties of thick tissues. Although NIR methods were first applied to breast diaphanography nearly 80 years ago, quantitative DOI methods employing time- or frequency-domain photon migration technologies have only recently been used for breast imaging (i.e. since the mid-1990s). In this research program we propose the formation of a flexible, multi-institutional "Network" composed of partnerships between leading, Academic, Industry and Government laboratories that have demonstrated expertise in Breast Cancer Research. Our broad goal is to advance new technology, Multi-Dimensional Diffuse Optical Imaging (MDDOI), that will dramatically improve breast cancer detection, clinical management, and quality of life for breast cancer patients. MD-DOI employs broadband technology both in spectral (approximately 650-1000 nm) and temporal (approximately IGHz) domains in order to separate absorption from scattering and quantify multiple molecular probes based on absorption or fluorescence contrast. Additional dimensionality is provided by integrating and co-registering MD-DOI functional information with Magnetic Resonance Imaging (MRI) and X-Ray mammography. Factors affecting critical MD-DOI issues, such as intrinsic and extrinsic conlrast mechanisms, quantitation of biochemical components, image formation/visualization, and multi-modality co-registration will be explored and defined in 3 research projects and delivered as usable translational technologies by three research resource cores. Based on these fmdings, a standardized MD-DOI platform will be developed that can be used as a stand-alone device or in conjunction with MRI and mammography. This technology will be tested, validated, and duplicated for translational use in multiple clinical sites: The University of Pennsylvania, The Massachusetts General Hospital (MGH), Dartmouth University, and The University of California, (Irvine and San Francisco). Clinical studies in each test site will involve coordination through their respective breast care centers housed in five NCI Comprehensive Cancer Centers. Pre-clinlcal animal studies will be performed using specially designed MD-DOI technology optimized for animal models and optical/MR/molecular imaging agents. The proposed Network will stimulate the development, validation, and standardization of new technologies, procedures, and analysis tools; as well as the formation of important multi-institutional collaborative relationships and commercial partners. This broad-based, multi-disciplinary effort will provide the community with new insight regarding the origins of breast disease and practical approaches for addressing several key challenges in breast cancer clinical management, including: detecting early disease, distinguishing between malignant and benign lesions, and understanding the impact of therapies (e.g. hormone replacement therapy (HRT) and neoadjuvant chemotherapy).